Adjuvant Pembrolizumab for the Treatment of Clear Cell Renal Cell Carcinoma: Five-year Results from the Phase III KEYNOTE-564 Study

BACKGROUND:The randomized phase III study KEYNOTE-564 (NCT03142334) established pembrolizumab after surgery as the standard of care for patients with clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence. Prior analyses showed significantly improved disease-free survival (DFS) and overall survival (OS) with adjuvant pembrolizumab versus placebo. We present results from the fourth prespecified interim analysis, with a minimum follow-up of five years. PATIENTS AND METHODS:Eligible adults with ccRCC at increased risk of recurrence were randomly assigned 1:1 to adjuvant pembrolizumab 200 mg or placebo every 3 weeks following nephrectomy or following nephrectomy and metastasectomy. Study treatment continued for ≤17 cycles (∼1 year), until recurrence, or until treatment discontinuation criteria were met. The primary endpoint was DFS per investigator assessment, and the key secondary endpoint was OS. Safety was a secondary endpoint. RESULTS:Overall, 994 participants were randomized to pembrolizumab (n = 496) or placebo (n = 498). Median time from randomization to data cutoff (September 25, 2024) was 70 months (range, 60-87). Pembrolizumab improved DFS versus placebo (hazard ratio [HR] 0.71, 95% CI 0.59-0.86); median DFS was not reached (NR) versus 68 months, and estimated 5-year DFS rates were 60.9% versus 52.2%, respectively. OS was improved with pembrolizumab over placebo (HR 0.66, 95% CI 0.48-0.90); median OS was NR for both arms with an estimated 5-year OS rate of 87.7% and 82.3%, respectively. DFS and OS benefits were consistent across key subgroups. Safety was largely unchanged since last analysis. CONCLUSIONS:After a median follow-up of 70 months, adjuvant pembrolizumab demonstrated sustained DFS and OS benefit and a safety profile consistent with prior analyses. These findings continue to support the use of adjuvant pembrolizumab in ccRCC at increased risk of recurrence.